This invention relates to novel fucosidase inhibitors. More particularly, the invention relates to the synthesis of .beta.-L-homofuconojirimycin and related 1-.beta.-C-substituted deoxymannojirimycins.
Both deoxynojirimycin (1) and .alpha.-homonojirimycin (2), the first example of a naturally occurring azapyranose analogue of a heptose recently isolated from Omphalea diandra L., are potent inhibitors of .alpha.-glucosidase activity. See Kite et al., Tetrahedron Lett. 29, 6483-6486 (1988). Iminoheptitols such as (2) provide the opportunity for the synthesis of a class of stable aza-disaccharides such as (3) which may confer additional potency and/or specificity in comparison with the corresponding azapyranose analogues such as deoxynojirimycin; for example, the .beta.-D-glucopyranosyl derivative (3) of .alpha.-homonojirimycin was first designed as a synthetic transition state inhibitor of .alpha.-glucosidases. See Liu, J. Org. Chem. 52, 4717 (1987). It is in clinical trials in relation to the treatment of diabetes mellitus. See Rhinehart et al., J. Pharmacol. Exptl. Therapeut. 241, 915-920 (1987).
1,5-Dideoxy-1,5-imino-L-fucitol, also referred to as deoxyfuconojirimycin (DFJ) (4), readily prepared from D-lyxonolactone [Fleet et al., J. Chem. Soc. Perkin Trans. 1, 665-666 (1989], is a very powerful and highly specific inhibitor of a number of mammalian .alpha.-L-fucosidases. Some fucosidase inhibitors have potential as antiretroviral agents. See Fleet et al., FEBS Lett. 237, 128-132 (1988); Karpas et al., Proc. Natl. Acad. Sci. USA 85, 9229-9233 (1988); and copending applications Ser. No. 07/248,461, filed Sept. 23, 1988, now U.S. Pat. No. 4,349,430 and Ser. No. 7/249,144, filed Sept. 26, 1988, now U.S. Pat. No. 4,999,360. ##STR1##